Cow milk is the most common cause of food allergy in the first year of life, with approximately 2.5% of newborns experiencing allergic reactions to cow milk during this time. While most infants with non-IgE-mediated cow milk allergy [CMA] 'outgrow' their sensitivity by the 3rd year of life, 15% of infants with IgE-mediated cow milk allergy retain their sensitivity into the second decade and 35% develop allergic reactions to other foods. IgE- and non-IgE-mediated mechanisms each appear to account for about one-half of milk hypersensitivity disorders in young children. Acute urticaria and atopic dermatitis are two forms of IgE-mediated skin reactions associated with CMA. A number of distinct cow milk-induced, non-IgE-mediated skin reactions associated with CMA. A number of distinct cow milk-induced, non-IgE-mediated [presumably cell-mediated] gastrointestinal hypersensitivities have been described. Milk-induced Enterocolitis Syndrome and Allergic Eosinophilic Gastroenteritis [AEG] are well characterized clinically, but the immunopathological basis of these two disorders is poorly understood. Milk proteins have been well characterized but there is little information regarding their roles inv various milk hypersensitivity disorders. We hypothesize that differences in immune antigen-processing and presenting of specific milk proteins result in the recognition of different B cell and T cell epitopes among milk-allergic patient groups and controls. We further hypothesize that patients "outgrowing" their clinical hypersensitivity will lose their ability to recognize "disease-associated epitopes". These hypotheses will be addressed 3 aims: (1) Patients with each of the well characterized CMA disorders will be recruited and followed prospectively. Both humoral and cellular responses to 4 well-characterized milk proteins will be evaluated. Cells from the peripheral blood, and skin and intestinal biopsies activated by milk proteins in vitro will be characterized as to phenotype, homing receptor positivity, and cytokine expression. (2) IgE- and IgG-binding epitopes of the 4 major milk proteins will be mapped uti9lizing sera from patients and control subjects. T cell epitopes will be established using PBMC and T-cells lines and clines established using PBMCs and will be mapped utilizing sera from patients and control subjects. T cell epitopes will be established using PBMCs and will be mapping utilizing sera from patients and control subjects. T cell epitopes will be established using PBMCs and T-cell lines and clones established from patients and controls. (3) Since approximately 50% of all milk allergic patients lose their clinical reactivity to milk in 2-3 years, patients will be followed prospectively to correlate changes n specific cells and their immunologic responses to "hypersensitivity-associated" epitopes. Characterization of distinct milk hypersensitivity reactions at a cellular and molecular level will provide new insights into the immunopathogenesis and future therapeutic strategies of food hypersensitivity disorders. This project will serve as a foundation for other projects in this proposal.